SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti-Trypanosoma brucei Agent

被引：7

作者：

Borsari, Chiara ^{[1
,7
]}

Santarem, Nuno ^{[2
,3
]}

Macedo, Sara ^{[2
,3
]}

Dolores Jimenez-Anton, Maria ^{[4
]}

Torrado, Juan J. ^{[4
]}

Isabel Olias-Molero, Ana ^{[4
]}

Corral, Maria J. ^{[4
]}

Tait, Annalisa ^{[1
]}

Ferrari, Stefania ^{[1
]}

Costantino, Luca ^{[1
]}

Luciani, Rosaria ^{[1
]}

Ponterini, Glauco ^{[1
]}

Gul, Sheraz ^{[5
]}

Kuzikov, Maria ^{[5
]}

Ellinger, Bernhard ^{[5
]}

Behrens, Birte ^{[5
]}

Reinshagen, Jeanette ^{[5
]}

Maria Alunda, Jose ^{[4
]}

Cordeiro-da-Silva, Anabela ^{[2
,3
,6
]}

Costi, Maria Paola ^{[1
]}

机构：

[1] Univ Modena & Reggio Emilia, Via Campi 103, I-41125 Modena, Italy

[2] Univ Porto, IBMC, P-4150180 Porto, Portugal

[3] Univ Porto, Inst Invest & Inovacao Saude, P-4150180 Porto, Portugal

[4] Univ Complutense Madrid, Madrid 28040, Spain

[5] Fraunhofer Inst Mol Biol & Appl Ecol Screening Po, D-22525 Hamburg, Germany

[6] Univ Porto, Fac Farm, Dept Ciencias Biol, P-4050313 Porto, Portugal

[7] Univ Basel, Dept Biomed, Mattenstr 28, CH-4058 Basel, Switzerland

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 04期

关键词：

Trypanosoma brucei; flavonol-like compounds; SAR studies; ADME-tox properties; neglected tropical diseases; IN-VIVO; DIMERIZATION; FLAVONOIDS; PARASITES; SCAFFOLD; ANALOGS; LEADS;

D O I：

10.1021/acsmedchemlett.8b00565

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Chemical modulation of the flavonol 2-(benzo[d] [1,3]dioxo1-5-y1)-chromen-4-one (1), a promising anti-Trypanosomatid agent previously identified, was evaluated through a phenotypic screening approach. Herein, we have performed structure activity relationship studies around hit compound 1. The pivaloyl derivative (13) showed significant anti-T. brucei activity (EC50 = 1.1 1iM) together with a selectivity index higher than 92. The early in vitro ADME-tox properties (cytotoxicity, mitochondria] toxicity, cytochrome P450 and hERG inhibition) were determined for compound 1 and its derivatives, and these led to the identification of some liabilities. The 1,3-benzodioxole moiety in the presented compounds confers better in vivo pharmacokinetic properties than those of classical flavonols. Further studies using different delivery systems could lead to an increase of compound blood levels.

引用

页码：528 / 533

页数：11

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